> When he and his colleagues looked at the individuals’ immune cells, they could see encounters with all sorts of viruses—flu, measles, mumps, chickenpox. But the patients had never reported any overt signs of infection or illness.
Given that the article goes on to talk about mild persistent inflammation, is it possible that these individuals are sometimes asymptomatic but still capable of carrying/transmitting viruses at least temporarily? The article talks about potentially immunizing healthcare workers during a future pandemic, but if this was just allowing people to never develop symptoms (and not have to leave work) while having low-grade infections, would we accidentally create a work-force of Typhoid Marys?
devmor · 1h ago
I am not a medical expert, but from what I read the last time I saw this being discussed, ISG15 deficiency also causes something called "infernopathy" that leads to inflammation across the entire body. I don't believe it's related to viral activity at all.
mapontosevenths · 56m ago
From TFA: "We only generate a small amount of these ten proteins, for a very short time, and that leads to much less inflammation than what we see in ISG15-deficient individuals,” Bogunovic says. “But that inflammation is enough to prevent antiviral diseases."
It seems that the goal is to learn to trigger the benefits, without triggering the bad parts. Which, should probably have been obvious to you without even bothering to read the article.
giancarlostoro · 2h ago
Wont viruses just adapt and now we've got worse viruses as a result? Isn't this kind of why doctors don't like to prescribe antibiotics too often, because they become ineffective in the long run.
I'm genuinely asking, I'm a simple software dev not a doctor.
thyristan · 2h ago
Maybe, maybe not. Antibiotic resistance develops because antibiotics are only somewhat deadly to bacteria, so natural selection can occur and bacteria develop resistance over time. There are some antibiotic/bacteria combinations where this doesn't happen, because the respective antibiotic is so deadly to that special kind of bacteria, that no survivors can pass on their slightly increased resistance.
And bacteria self-replicate, whereas a virus needs to infect a cell and be reproduced by that cell. Some antiviral mechanisms attack the reproduction proteins that the human cells use, which the virus cannot do without. And the human cells don't have reproductive pressure to replicate viruses, quite the contrary.
francisofascii · 14m ago
Is a fair analogy, antibiotics kill, whereas antivirals use birth control? So viruses would have to find a way to circumvent the replication inhibitors or potentially find a noval way to replicate.
kristjank · 2h ago
Antibiotics are related to bacteria, which have different mutation mechanisms than viruses. I'm also a tech guy, so someone may correct me.
Also, this seems to influence the human end to make protective material, not act on the viruses directly.
busyant · 2h ago
Viruses can acquire resistance by mutation. This has been well established for decades.
FWIW, I was trained as a bacterial geneticist and routinely used bacteriophage (viruses that infect bacteria) with various resistance mutations.
Viral mutations are not restricted to viruses that infect bacteria.
edit: in fact, fundamental aspects of the genetic code were determined by analyzing and exploiting viral mutations.
Is it really true that we have “worse” viruses, or that they are adapting to our modern antibiotic regime & reverting to the status quo?
XorNot · 1h ago
Antibiotics have never killed any viruses ever. They are exclusively for treating bacterial infections (which are generally worse by a lot).
tiahura · 1h ago
Azithromycin (rhinovirus, influenza A, Zika), clarithromycin (influenza A, rhinovirus), doxycycline (dengue, Zika), minocycline (West Nile), teicoplanin/dalbavancin (Ebola, MERS/SARS-CoV and SARS-CoV-2), rifampin/rifamycins (orthopoxviruses), aminoglycosides (HSV-2, influenza A, Zika), salinomycin/monensin (influenza A/B, coronaviruses incl. SARS-CoV-2), nanchangmycin (Zika, West Nile, dengue, chikungunya), nitroxoline (mpox), and some fluoroquinolones have all shown antiviral properties.
And no, strep throat is not worse than ebola.
bee_rider · 30m ago
I think they used “generally” on purpose, to make a general observation. Of course, there exist viral infections that are worse than the most common bacterial ones.
There’s some ambiguity in their comment because it isn’t obvious what we’re sort of… averaging over, but I think they clearly don’t mean that there no serious viral infections exist.
aredox · 2h ago
1) Viruses don't adapt instantly nor perfectly - that's why viruses can be animal-specific. Influenza (or recently SARS-CoV) are famous because they are malleable enough to adapt to new hosts, human or animal, within a few months or years, but not all viruses have this ability.
2) To further illustrate, some viruses have been nearly eliminated with a single vaccine. Polio didn't manage to adapt before going almost extinct. And a good reason why is:
3) Viruses can only evolve inside contaminated hosts. If you find a cure that stops quickly the virus from multiplying and contaminating, you are also curtailing its ability to adapt. A contaminated host is a giant casino machine, allowing the virus to mutate until it hits a new evolutionary step. A strong enough vaccine or treatment is like throwing out the virus before it has time to play much.
tialaramex · 1h ago
Two viruses have been entirely eliminated in the wild, one (Smallpox) still exists in government research facilities the other (Rinderpest) I believe is just gone because it wasn't useful as a direct weapon (humans aren't affected) and nobody actually wants Rinderpest, it was just killing cattle and while poor farmers need their cattle or they'll starve the rich want to drink milk and eat steak so they weren't keen on this virus either and helped fund its eradication.
quotemstr · 1h ago
Of course. Given unlimited time, viruses will develop resistance. Resistance = evolution = descent + modification + selection. You can quibble about whether viruses are alive, but they definitely evolve.
But so what? Anti-pathogen drugs are useful in the period during which resistance hasn't become universal, and if and when it comes a problem, we'll have other drugs.
Besides: sometimes you get lucky and the virus goes extinct before it can develop resistance (e.g. smallpox)
MengerSponge · 44m ago
That's not really true. Evolution is constrained by physics, so while bacteria can evolve to live in 100C water, they can't evolve to live in molten magma, or the surface of the sun. Similarly, they can evolve to live off of isopropyl alcohol, but they can't evolve resistance to sufficiently concentrated bleach (sodium hypochlorite).
capitainenemo · 8m ago
I'm not sure what you consider "sufficiently concentrated" but some existing viruses (which form spores) can already survive a 1% sodium hypochlorite solution cleaning, which is pretty crazy-high. At that point you're risking damage to surfaces/skin. Doesn't seem impossible it could go higher if bleach exposure was consistently selected for.
inka · 1h ago
And the part where he says people with this mutation are more prone to bacterial infections is not worrying, because…?
In a world of more and more antibiotic resistant bacteria, that does not seem like a good trade-off…
empath75 · 30m ago
Probably the issue is microphages being wiped out which allows bacteria to thrive. But you wouldn't take this _all the time_, only when you had a specific viral infection to get rid of.
yablak · 2h ago
Sounds like the first few scenes of every Zombie movie and TV show ever...
oaiey · 1h ago
Indeed. Or an Utopia. But sentencing on that is still open
jihadjihad · 1h ago
I like the turn of phrase "sentencing" here. The jury gave its verdict, guilty as all hell, and now we're ready for the sentencing hearing, Your Honor.
IIAOPSW · 1h ago
There are things that are wrong and there are things that are crimes and it is up to those on the bench to appreciate the difference.
When you get a viral infection, immune cells make a signalling protein called a IFN-1 (Type I Interferon) cytokine, and this flips a boolean flag to True on a bunch of genes (interferon-stimulated genes or ISGs) that produce a bunch of proteins (hundreds) that control the infection. ISG15 is one of them and its role appears to be to downregulate and to limit the inflammation.
The paper title refers to a ISG15 deficiency, meaning if you are dificient in ISG15 that inflamation limitation goes away. But the paper is actually about how in people that naturally have a ISG15 deficiency, there is an always-on low level expression of some of these pro-inflamation genes. So they take that as a safe level.
The did RNA sequencing on experimental ISG15 deficient cells and from heatlhy individuals, identified the mutations, narrowed down to 10 genes (antiviral ones not inhibitors) that in combination significantly inhibited viral replication. They stuck the RNA for such genes in lipid nanoparticles such that they enter host cells, whose ribosomes happily read the RNA like a turing head reads a tape in base 20 and produce proteins encoded by these genes, similar to how the mRNA vaccine works.
So why not dose with the IFN-I directly? Three referenced papers show its "poorly tolerated with significant side effects" and all those downregulators that get expressed limit the inflammation response.
Disclaimer: IANAB (not a biologist) corrections might be due..
vprcic · 1h ago
The prospect of being able to use this against viruses like the one causing rabies is pretty exciting!
account42 · 1h ago
Don't we already have treatments for the rabies virus but the problem is that it's too late once the virus gets to the central nervous system which is when symptoms show? How would this new antiviral be different?
tovej · 2h ago
Interesting, and potentially very good. But I can't help but wonder, like at least one other commenter, that this might have unexpected effects if applied at a larger scale. I know some viruses kill bacteria for instance. I don't know, something about universal applicability makes me a little uneasy.
XorNot · 1h ago
Bacteriophages don't infect things which aren't bacteria.
In fact they're so absurdly specific that while you could bathe in a solution of them and not get sick, they also frequently fail to infect slightly different members of the same species, which is why ultimately they never become antibiotic alternatives: having the right one on hand ranges from difficult to impossible.
quotemstr · 1h ago
Broad-based inflammation delivered by lipid nanoparticle chock full of mRNA: what could possibly go wrong? I'll stick with monoclonal antibodies, thanks.
Oh, and here's what the ISG15 deficiency (the condition these mRNAs are there to simulate) does:
> Patients present...with infectious, neurologic or dermatologic features. Basal ganglia calcification is observed in all patients... The basal ganglia calcifications may cause epileptic seizures... The IFN-I inflammation may also manifest early in life as ulcerative skin lesions in the armpit, groin and neck regions. Finally, ISG15-deficiency leads to mendelian susceptibility to mycobacterial disease... [t]hese infections present as fistulizing lymphadenopathies and respiratory symptoms following BCG vaccination.
Given that the article goes on to talk about mild persistent inflammation, is it possible that these individuals are sometimes asymptomatic but still capable of carrying/transmitting viruses at least temporarily? The article talks about potentially immunizing healthcare workers during a future pandemic, but if this was just allowing people to never develop symptoms (and not have to leave work) while having low-grade infections, would we accidentally create a work-force of Typhoid Marys?
It seems that the goal is to learn to trigger the benefits, without triggering the bad parts. Which, should probably have been obvious to you without even bothering to read the article.
I'm genuinely asking, I'm a simple software dev not a doctor.
And bacteria self-replicate, whereas a virus needs to infect a cell and be reproduced by that cell. Some antiviral mechanisms attack the reproduction proteins that the human cells use, which the virus cannot do without. And the human cells don't have reproductive pressure to replicate viruses, quite the contrary.
FWIW, I was trained as a bacterial geneticist and routinely used bacteriophage (viruses that infect bacteria) with various resistance mutations.
Viral mutations are not restricted to viruses that infect bacteria.
edit: in fact, fundamental aspects of the genetic code were determined by analyzing and exploiting viral mutations.
https://en.wikipedia.org/wiki/Crick,_Brenner_et_al._experime...
And no, strep throat is not worse than ebola.
There’s some ambiguity in their comment because it isn’t obvious what we’re sort of… averaging over, but I think they clearly don’t mean that there no serious viral infections exist.
2) To further illustrate, some viruses have been nearly eliminated with a single vaccine. Polio didn't manage to adapt before going almost extinct. And a good reason why is:
3) Viruses can only evolve inside contaminated hosts. If you find a cure that stops quickly the virus from multiplying and contaminating, you are also curtailing its ability to adapt. A contaminated host is a giant casino machine, allowing the virus to mutate until it hits a new evolutionary step. A strong enough vaccine or treatment is like throwing out the virus before it has time to play much.
But so what? Anti-pathogen drugs are useful in the period during which resistance hasn't become universal, and if and when it comes a problem, we'll have other drugs.
Besides: sometimes you get lucky and the virus goes extinct before it can develop resistance (e.g. smallpox)
My summary for programmers:
When you get a viral infection, immune cells make a signalling protein called a IFN-1 (Type I Interferon) cytokine, and this flips a boolean flag to True on a bunch of genes (interferon-stimulated genes or ISGs) that produce a bunch of proteins (hundreds) that control the infection. ISG15 is one of them and its role appears to be to downregulate and to limit the inflammation.
The paper title refers to a ISG15 deficiency, meaning if you are dificient in ISG15 that inflamation limitation goes away. But the paper is actually about how in people that naturally have a ISG15 deficiency, there is an always-on low level expression of some of these pro-inflamation genes. So they take that as a safe level.
The did RNA sequencing on experimental ISG15 deficient cells and from heatlhy individuals, identified the mutations, narrowed down to 10 genes (antiviral ones not inhibitors) that in combination significantly inhibited viral replication. They stuck the RNA for such genes in lipid nanoparticles such that they enter host cells, whose ribosomes happily read the RNA like a turing head reads a tape in base 20 and produce proteins encoded by these genes, similar to how the mRNA vaccine works.
So why not dose with the IFN-I directly? Three referenced papers show its "poorly tolerated with significant side effects" and all those downregulators that get expressed limit the inflammation response.
Disclaimer: IANAB (not a biologist) corrections might be due..
In fact they're so absurdly specific that while you could bathe in a solution of them and not get sick, they also frequently fail to infect slightly different members of the same species, which is why ultimately they never become antibiotic alternatives: having the right one on hand ranges from difficult to impossible.
Oh, and here's what the ISG15 deficiency (the condition these mRNAs are there to simulate) does:
> Patients present...with infectious, neurologic or dermatologic features. Basal ganglia calcification is observed in all patients... The basal ganglia calcifications may cause epileptic seizures... The IFN-I inflammation may also manifest early in life as ulcerative skin lesions in the armpit, groin and neck regions. Finally, ISG15-deficiency leads to mendelian susceptibility to mycobacterial disease... [t]hese infections present as fistulizing lymphadenopathies and respiratory symptoms following BCG vaccination.
Yeah, about those antiviral superpowers...
His reputably published, peer reviewed, work can be found here: https://www.science.org/doi/10.1126/scitranslmed.adx5758